Throughout this application, various references are cited in parentheses to describe more fully the state of the art to which this invention pertains. The disclosure of these references are hereby incorporated by reference into the present disclosure.
Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.
Tyrosine kinases can be categorized as receptor type or non-receptor type. Receptor type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular.
The receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. Approximately 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily is comprised of EGFR, HER2, HER3, and HER4. Ligands of this subfamily of receptors include epithelial growth factor, TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamily includes the PDGF-α and β receptors, CSFIR, c-kit and FLK-II. The FLK family is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1) (Plowman et al., DN&P 7(6):334-339, 1994, which is hereby incorporated by reference).
The non-receptor type of tyrosine kinases are also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis (Bolen Oncogene, 8:2025-2031 (1993), which is hereby incorporated by reference).
Both receptor-type and non-receptor type tyrosine kinases are implicated in cellular signalling pathways leading to numerous pathogenic conditions, including a variety of cancers. For example, the Bcr-Abl tyrosine kinase is the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). Inappropriate Bcr-Abl activity is also demonstrated in murine myeloid cells as well as Bcr-Abl positive leukemia lines derived from CML patients in blast crisis.
A variety of tyrosine kinase inhibitors have been developed for the treatment of different types of clinical conditions. See for example U.S. Pat. Nos. 5,543,520 and 5,521,184.
It is therefore desirable to identify additional compounds which specifically inhibit, regulate and/or modulate the signal transduction of tyrosine kinases and in particular those tyrosine kinases involved in various malignancies in order to develop novel strategies for treatment.